Viral infections are usually treated with substances targeting viral proteins, e.g. influenza is treated with M2-membrane protein inhibitors (adamantin and rimantadin) or neuraminidase inhibitors (oseltamivir and zanamivir); HIV is treated with HIV protease inhbitors, reverse transcriptase inhibitors (nucleoside and non-nucleoside analoga), fusion inhibitors (blocking the viral transmembrane protein gp41) or cell entry inhibitors; HCV is treated by a combination of ribavirin and interferone alpha, where ribavirin as a nucleoside analogue inhibits the viral polymerase, and interferone alpha activates the host immune system; HBV is treated with pegylated interferone alpha and/or nucleoside or nucleotide analoga.
However, treatment of these viral diseases is not satisfactory due to the high mutation rate of viruses and the thus resulting lack of efficacy of presently known medications. Moreover, severe side effects caused by interaction with host factors or by incompatibility of treatments for patients who are infected with two or several different viruses occur regularly. In view of the viruses' abilities to quickly adapt to new selection pressures caused by substances targeting viral proteins, new treatment options for viral diseases are urgently required. A new approach to circumvent the selection pressure on viruses and thus avoid the generation of resistances is the targeting of host cell factors vital for the viral replication cycle.
The active metabolite of leflunomide, a DHODH inhibitor with a completely different structure has been discussed and tested lately in several viral infection models as well as in infected patients (Gabriel T. Meister, dissertation Ohio State University 2005; Chong et al. Am. J. Transplant 2006 6(1): 69-75), however, antiviral activity is largely attributed to the inhibition of protein kinases which results in inhibition of phosphorylation of viral proteins. Moreover, administration of uridine in viral plaque assays did not affect the reduction of viral loads in a cytomegalovirus (CMV) model; an inhibitor exerting its activity by the inhibition of DHODH, however, according to the above cited publications would be expected to lose its inhibitory potential when the assay is supplemented with uridine.
The compounds to which this invention relates have been described as DHODH inhibitors before (WO 03/006425, WO 04/056746, WO 04/056797, WO04056747, WO 08/077639, WO 09/021696), and the treatment of diseases caused by viral infections has been mentioned. These compounds are more active DHODH inhibitors when compared to the active metabolite of leflunomide and do not inhibit protein kinases at physiologically relevant levels. Furthermore, it has been shown that the antiviral activity of compounds from this invention can be reversed by addition of uridine (Marshall et al., Antiviral Research 100 (2013) 640-648). Therefore, it is concluded that the antiviral activity of compounds to which this invention relates is based on inhibition of DHODH. In contrast, for the active metabolite of leflunomide antiviral activity is largely attributed to the inhibition of protein kinases.
The pathogenity of viruses heavily relies on host cell machinery for replication, leading to a high need of nucleobase building blocks due to the high replication rate of the viruses. Unexpectedly it has now been found, that the inhibition of DHODH, which leads to an inhibition of the de novo biosyntheses of pyrimidines can be exploited to suppress the replication of certain viruses.